The hippocampus is essential for our ability to encode memories for facts, places, and events. My long-term research goal is to understand how neural activity in specific neural circuits gives rise to complex behaviors, and how these circuits and behaviors are altered in pathological states. In this research proposal, we specifically consider the basis of neural activity at hippocampal subfield CA1, the output region of the hippocampus. CA1 has traditionally been studied as having two main inputs: layer III of the entorhinal cortex, or EC3, and hippocampal subfield CA3. These inputs are thought to convey information to CA1 about current experience (EC3) and internally stored representations (CA3). While these upstream regions have been extensively studied, little is known about how CA1 integrates input from CA3 and EC during learning. We believe a poorly characterized neighboring region called CA2 may have a central and rapid role in this integration. To address this possibility, we will use multi-electrode implants to record neural activity in CA1, CA2, and CA3 of rats engaged in a hippocampus-dependent memory task (Aim 1 and Aim 2). We will also use precise tools for electrophysiological manipulation to establish causal roles of CA2 in hippocampal neural activity patterns (Aim 2), representations (Aim 2B), and learning (Aim 2B). Our specific aims are: Specific Aim 1: To test the hypothesis that CA2 activation precedes both EC3- and CA3- driven network patterns at CA1. Specific Aim 2: To test the hypothesis that CA2 controls EC3- and CA3- driven network patterns at CA1. Specific Aim 2A: To test the hypothesis that CA2 activation is sufficient for initiating CA3- driven network patterns at CA1. Specific Aim 2B: To test the hypothesis that CA2 activity is necessary for EC3- driven network patterns and representations at CA1, and for normal hippocampal memory function. Accomplishing these Specific Aims will reveal how information is processed in a relatively neglected part of the hippocampal circuit, in addition to providing functional roles for CA2, a region of the brain whose role has never been established. This research is necessary for understanding the origins and consequences of hippocampal dysfunction, as encountered in the range of neuropsychiatric disorders linked to the hippocampus. These disorders include schizophrenia, mood disorders, autism spectrum disorders, and dementia. PUBLIC HEALTH RELEVANCE: The hippocampus is a brain structure that is critical for our ability to remember new facts, places, and events. Dysfunction of the hippocampus is associated with age-related memory loss, autism spectrum disorders, schizophrenia, depression, and addiction - yet we do not understand how hippocampal function contributes to the complex behavioral changes observed in these disorders. The proposed research will help us better understand the normal functioning of the hippocampus, specifically by characterizing a poorly understood region of the hippocampus known as CA2, and thus provide the basis for more effective treatments of these disorders involving the hippocampus.